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Respiratory chain deficiency slows down cell‐cycle progression via reduced ROS generation and is associated with a reduction of p21 CIP1/WAF1
Author(s) -
Schauen Matthias,
Spitkovsky Dimitry,
Schubert Jens,
Fischer Jürgen H.,
Hayashi JunIchi,
Wiesner Rudolf J.
Publication year - 2006
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.20711
Subject(s) - cell cycle , respiratory chain , biology , reactive oxygen species , mitochondrial ros , cell growth , phenocopy , microbiology and biotechnology , protein kinase b , mitochondrial respiratory chain , mapk/erk pathway , mitochondrion , apoptosis , signal transduction , biochemistry , phenotype , gene
We have used HeLa cells without mitochondrial DNA (ρ 0 ‐cells) and transient ρ 0 ‐phenocopies, obtained from wild‐type cells by short‐term treatment with ethidium bromide, to analyze how the absence of a functional mitochondrial respiratory chain slows down proliferation. We ruled out an energetic problem (ATP/ADP content) as well as defective synthesis of pyrimidine, iron‐sulfur clusters or heme as important causes for the proliferative defect. Flow cytometric analysis revealed that reactive oxygen species were reduced in ρ 0 ‐cells and in ρ 0 ‐phenocopies, and that, quite unusually, all stages of the cell cycle were slowed down. Specific quenching of mitochondrial ROS with the ubiquinone analog MitoQ also resulted in slower growth. Some important cell‐cycle regulators were reduced in ρ 0 ‐cells: cyclin D3, cdk6, p18 INK4C , p27 KIP1 , and p21 CIP1/WAF1 . In the ρ 0 ‐phenocopies, the expression pattern did not fully duplicate the complex response observed in ρ 0 ‐cells, and mainly p21 CIP1/WAF1 was downregulated. Activities of the growth regulatory PKB/Akt and MAPK/ERK‐signaling pathways did not correlate with proliferation rates of ρ 0 ‐cells and ρ 0 ‐phenocopies. Our study demonstrates that loss of a functional mitochondrial electron transport chain inhibits cell‐cycle progression, and we postulate that this occurs through the decreased concentration of reactive oxygen species, leading to downregulation of p21 CIP1/WAF1 . J. Cell. Physiol. 209: 103–112, 2006. © 2006 Wiley‐Liss, Inc.